POS0702 ANTI-RHEUMATIC TREATMENT ALTERS PFKFB3 EXPRESSION, KEY OF GLYCOLYSIS, IN CD14+ MONOCYTES OF RA PATIENTS, WHICH CONTRIBUTES TO DISSIMILARITIES OF THE IFNg-SIGNATURE
Authors: M. Erlandsson, E. Malmhäll-Bah, K. M. Andersson, S. Töyrä Silfverswärd, R. Pullerits, M. I. Bokarewa
Journal: Annals of the Rheumatic Diseases (2022)

Background Interferon-gamma (IFNαnterferon-gamma (IFNRheumatology clinic, Gothenburg, Swedenh, Göteborg, Swedenmonocytes of RA patients, which contributes to dissimilarities of the IFNg-signature Peter C. Taylor Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, mulation is energy consuming and often demands metabolic adaptation of a cell by switching glucose metabolism from the tricarboxylic acid cycle (TCA) to the pentose phosphate pathway (PPP) alternative of glycolysis that dramatically increases glucose intake. Fructose-2,6-biphosphatase 3 (coded by PFKFB3 ) has been identified as the rate-limiting regulator of glucose metabolism suppressed in leukocytes of RA patients (2). Objectives To study effect of anti-rheumatic treatment on the cellular energy metabolism of CD14 + mononuclear cells and its connection to the phenotype and IFNαmononuclear. Methods CD14 + cells were sorted from the peripheral blood of the randomly recruited 60 RA patients (mean age 59.6y, DD 13.8y). The cells were LPS activated for 2h and submitted to RNA sequencing (RNAseq, IluminaNextseq). The patients were divided by actual DMARD treatment into those who had no DMARDs (n=8), methotrexate (MTX) only (n=15), biologics (MTX+aTNF n=12, MTX+RTX n=4) and JAK-inhibitors (JAKi, n=24). Differentially expressed gene (DEG) analysis between the groups was performed in R-studio, Bioconductor package, DESeq2. Reported IFN signatures (1) were combined in a set of 51 IFN signature genes (ISG) and analyzed in relation to the transcriptomic profile behind the cellular energy metabolism and DMARD treatment. Results MTX and JAKi but not biologics make a significant and opposing contribution of the transcriptomic of energy metabolism in CD14 + cells. MTX-treated patients had significantly higher levels of the rate-limiting enzyme of glycolysis PFKFB3 and PGAM1 compared to those with no DMARDS, which normalized aerobic glycolysis by increasing expression of the pyruvate dehydrogenase complex proteins PDHA1 , PHDX and PDK3 linking glycolysis with TCA and decreasing PPP enzymes PGLS , RPIA and TKT . In contrast, PFKFB3 was suppressed in patients treated with JAK-inhibitors compared to those treated with MTX (cor.p=1.32e-8), which significantly activated glycolysis downstream of PFKFB3 and shunting metabolism to PPP inducing expression of G6PD (cor.p=5.0e-92) and PGLS (cor.p=3.1e-46) and increased the major glucose transporter SLC2A1 (cor.p=1.11e-24). These differences in glucose metabolism were linked to divergent phenotype of CD14 + cells being short-lived CD14 int CD11c hi cells and IL6 producing in MTX-treated patients and long-lived mature CD14 hi CD11b hi CX3CR1 hi cells and IFNαcells and IFN producing in MTX-treated pa + cells of JAKi-treated patients expressed low levels of STAT1 and ISGs compared to MTX-treated patients. Conclusion DMARD treatment har divergent effect on glycolysis of CD14 + cells, acting through PFKFB3. This has significant impact on the phenotype of CD14 + cells and inflammatory ability. References [1]Lamot L. Et.al. Clin Exp Rheumatol 2019, 37, 1077. [2]Yang Z. et al, Science Translational Medicine 2016, 8, 331, 331ra38. Disclosure of Interests None declared